N6-2-(4-aminophenyl)ethyl-adenosine enhances the anticonvulsive activity of antiepileptic drugs.

N6-2-(4-Aminophenyl)ethyl-adenosine (APNEA, a non-selective agonist of the adenosine A3 receptors), at the subprotective dose of 1 mg/kg against electroconvulsions, significantly potentiated the anticonvulsive action of phenobarbital, diphenylhydantoin and valproate against maximal electroshock, being ineffective at lower doses. APNEA (0.0039-1 mg/kg) also enhanced the protective activity of carbamazepine. Aminophylline (5 mg/kg) and 8-cyclopentyl-1,3-dimethylxanthine (8-CPX, 5 mg/kg), reversed the APNEA (1 mg/kg)-induced enhancement of the anticonvulsive action of phenobarbital, diphenylhydantoin and valproate, but not that of carbamazepine produced by APNEA at 0.0039 mg/kg. The adenosine agonist did not alter the plasma levels of antiepileptic drugs studied, so a pharmacokinetic interaction is not probable. Finally, APNEA (0.0156 and 1 mg/kg) administered alone or in combination with carbamazepine significantly decreased the body temperature and impaired long-term memory. Our results suggest that APNEA at low doses potentiates the protective activity of carbamazepine most likely through the A subtype of adenosine receptors. At higher doses, APNEA seems to enhance the anticonvulsive effect of other antiepileptics via adenosine A1 receptors.